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Metabolism of trabectedin (ET-743, Yondelis™) in patients with advanced cancer

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Abstract

Purpose

Trabectedin (ET-743, Yondelis™) is a novel anti-cancer drug currently undergoing phase II–III evaluation, that has shown remarkable activity in pre-treated patients with soft tissue sarcoma. Despite extensive pharmacokinetic studies, the human disposition and metabolism of trabectedin remain largely unknown. We aimed to determine the metabolic profile of trabectedin and to identify its metabolites in humans.

Methods

We analysed urine and faeces (the major excretory route) from eight cancer patients after a 3 or 24 h intravenous administration of [14C]trabectedin. Using liquid chromatography with tandem quadrupole mass spectrometric detection (LC-MS/MS) and radiochromatography with off-line radioactivity detection by liquid scintillation counting (LC-LSC), we characterised the metabolic profile in 0–24 h urine and 0–120 h faeces.

Results

By radiochromatography, a large number of trabectedin metabolites were detected. Incubation with β-glucuronidase indicated the presence of a glucuronide metabolite in urine. Trabectedin, ET-745, ET-759A, ETM-259, ETM-217 (all available as reference compounds) and a proposed new metabolite coined ET-731 were detected using LC-MS/MS. The inter-individual differences in radiochromatographic profiles were small and did not correlate with polymorphisms in drug-metabolising enzymes (CYP2C9, 2C19, 2D6, 2E1, 3A4, GST-M1, P1, T1 and UGT1A1 2B15) as determined by genotyping.

Conclusions

Trabectedin is metabolically converted to a large number of compounds that are excreted in both urine and faeces. In urine and faeces we have confirmed the presence of trabectedin, ET-745, ET-759A, ETM-259, ETM-217 and ETM-204. In addition we have identified a putative new metabolite designated ET-731. Future studies should be aimed at further identification of possible metabolites and assessment of their activity.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066, Amsterdam, The Netherlands

    Jan H. Beumer, Hilde Rosing, Michel J. X. Hillebrand, Tessa M. Bosch & Jos H. Beijnen

  2. Departments of Medical Oncology and Experimental Therapy, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jeany M. Rademaker-Lakhai & Jan H. M. Schellens

  3. PharmaMar, Human Pharmacology, Colmenar Viejo, Madrid, Spain

    Luis Lopez-Lazaro

  4. Department of Biomedical Analysis, Division of Drug Toxicology, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens & Jos H. Beijnen

  5. The Hillman Cancer Center, Research Pavilion, G.27d, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA

    Jan H. Beumer

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  1. Jan H. Beumer
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  2. Jeany M. Rademaker-Lakhai
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  3. Hilde Rosing
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Correspondence to Jan H. Beumer.

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Beumer, J.H., Rademaker-Lakhai, J.M., Rosing, H. et al. Metabolism of trabectedin (ET-743, Yondelis™) in patients with advanced cancer. Cancer Chemother Pharmacol 59, 825–837 (2007). https://doi.org/10.1007/s00280-006-0342-2

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  • DOI: https://doi.org/10.1007/s00280-006-0342-2

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